This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted across three institutions: Xiyuan Hospital of the China Academy of Chinese Medical Sciences, the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, and the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine. A total of 78 patients diagnosed with NERD characterized by spleen deficiency and damp-heat syndrome were enrolled in the trial. Participants were randomly assigned to either the experimental group or the control group, with each group consisting of 39 individuals.

To minimize heterogeneity across the three sub-centers, several measures were implemented: (1) standardized protocols: a unified trial protocol detailing patient recruitment, diagnostic criteria, randomization, treatment administration, and outcome assessments was followed at all centers; (2) investigator training: all TCM practitioners and clinical investigators underwent centralized training sessions led by the principal investigator. These sessions emphasized consistency in diagnosis, treatment, and data collection processes; (3) harmonized interventions: The same batch of JQ Granules and placebo was used at all centers, ensuring uniform quality and preparation of interventions; (4) blinded outcome assessment: all outcome assessments were conducted by investigators blinded to group allocation, reducing subjective bias across centers; (5) centralized data management: all data from the sub-centers were collected and managed in a centralized database, with periodic audits conducted to ensure data consistency and integrity.

The trial design encompassed a 1-week run-in period, followed by a 4-week double-blind treatment phase, and concluded with a 4-week follow-up period. All participants provided informed consent prior to enrollment, adhering to ethical standards.

During the run-in period, patients were assessed for eligibility and prepared for the treatment phase. The specific activities during this period included: (1) washout of acid-suppressing medications: participants who were taking PPIs or other acid-suppressive therapies were required to undergo a washout period of 3 days, during which these medications were gradually tapered. This ensured that symptoms were not masked by prior treatments and reflected the true severity of NERD. (2) baseline symptom assessment: at the start of the run-in period, all participants underwent a thorough assessment of their symptoms using the symptom scores. This helped establish baseline levels of reflux, heartburn, and other related symptoms, ensuring that patients were suitable for randomization and could be compared effectively across the treatment groups. (3) confirmation of eligibility: throughout the run-in period, participants were monitored for compliance with the inclusion criteria, including the negative gastroscopy results and absence of any other conditions, such as functional heartburn or reflux hypersensitivity, confirmed by multichannel intraluminal impedance-pH monitoring. Only those who remained eligible after this period proceeded to the treatment phase. (4) patient education and compliance: participants were educated on the study protocol, including the importance of adhering to the treatment schedule and keeping symptom diaries. Their compliance with these instructions was monitored through regular check-ins and follow-ups to ensure the consistency of their data.

Eligibility for the study required a confirmed diagnosis of NERD with spleen deficiency and damp-heat syndrome, as diagnosed and treated at the participating institutions between July 2020 and December 2021.

For the diagnosis of NERD, patients were required to present gastroscopy reports from Grade III Class A hospitals confirming negative endoscopic findings, with the report being issued within the past year. This one-year time frame was selected based on evidence suggesting that most GERD patients (75%−97%) maintain a stable clinical phenotype over time (18), making it reasonable to assume that endoscopic findings within this period accurately reflect the patient's current condition. Additionally, multichannel intraluminal impedance-pH monitoring was conducted on those with negative endoscopic results who were off PPI therapy, to exclude conditions such as functional heartburn and reflux hypersensitivity.

Information regarding spleen deficiency and damp-heat syndrome was collected by a senior TCM practitioner, who held an associate professor rank or higher. These practitioners were rigorously trained and supervised by the principal investigator to ensure consistency and accuracy in diagnosis.

The research protocol received approval from the Ethics Committee of Xiyuan Hospital, China Academy of Chinese Medical Sciences (Approval Number: 2020XLA009-3). The study was conducted in accordance with the Helsinki Declaration, relevant Chinese regulations, and clinical trial norms. The trial is registered with the North American Clinical Trial Data Center (ClinicalTrials.gov) under the registration number NCT04324138.

The criteria for diagnosing NERD were established based on the “Consensus Opinions on Gastroesophageal Reflux Disease in China (2006·10 Sanya)” and the “Expert Consensus Opinions on Gastroesophageal Reflux Disease in China 2014” (19, 20).

Inclusion criteria for study participants included: (1) fulfillment of the diagnostic criteria for NERD; (2) age between 18 and 70 years; (3) meeting TCM diagnostic criteria for spleen deficiency with damp-heat syndrome in NERD (Supplementary Table 1); (4) provision of informed consent and willingness to undergo the specified treatment regimen.

Exclusion criteria comprised: (1) presence of active peptic ulcers, gastrointestinal bleeding, severe gastric mucosal dysplasia, or suspected gastrointestinal tumors; (2) conditions such as distal esophageal spasm, nutcracker esophagus, achalasia, or post-achalasia surgery states; (3) functional heartburn or reflux hypersensitivity; (4) other organic diseases of the digestive system (e.g., acute or chronic pancreatitis, liver cirrhosis) or systemic diseases affecting gastrointestinal motility (e.g., scleroderma, hyperthyroidism, diabetes, chronic renal insufficiency, psychiatric and neurological disorders); (5) severe diseases of major organs, including the heart, liver, and kidneys, as well as hematological diseases and tumors; (6) pregnancy and lactation; (7) history of neurological or psychiatric disorders; (8) known allergies to the medications used in the study; (9) current participation in other clinical trials or those who have participated in such trials within the last 4 weeks.

The JQ granules and placebo used in this trial were sourced from China Resources Sanjiu Medical & Pharmaceutical Company Limited. Both the granules and placebo were processed and manufactured uniformly by the same pharmaceutical company to ensure consistency in appearance and taste, maintaining the integrity of the double-blind study design. The JQ granules consisted of 10 herbal ingredients, whose full botanical names, authorities, plant families, pharmacopeial drug names, and drug-extract ratios are as follows: Codonopsis pilosula (Franch.) Nannf. [Campanulaceae; Codonopsis Radix]—Drug-extract ratio: 5:1; Atractylodes lancea (Thunb.) DC. [Asteraceae; Atractylodis Rhizoma]—Drug-extract ratio: 5:1; Perilla frutescens (L.) Britton [Lamiaceae; Perillae Folium]—Drug-extract ratio: 20:1; Eupatorium fortunei Turcz. [Asteraceae; Eupatorii Herba]—Drug-extract ratio: 10:1; Citrus aurantium L. [Rutaceae; Aurantii Fructus]—Drug-extract ratio: 10:1; Scutellaria baicalensis Georgi [Lamiaceae; Scutellariae Radix]—Drug-extract ratio: 10:1; Coptis chinensis Franch. [Ranunculaceae; Coptidis Rhizoma]—Drug-extract ratio: 10:1; Sepiella maindroni de Rochebrune [Sepiidae; Sepiae Endoconcha (Cuttlebone)]—drug-extract ratio: 10:1; Massa medicata fermentata (Shenqu) [Traditional Fermented Product; Massa Medicata Fermentata]—Drug-extract ratio: 5:1; and Amomum villosum Lour. [Zingiberaceae; Amomi Fructus Rotundus]—Drug-extract ratio: 20:1. The final drug-extract ratio for the JQ granule product is approximately 7.76:1. These details are as previously described (15).

The chemical composition of the JQ granules was analyzed using two analytical fingerprinting methods. High-performance liquid chromatography was employed for the separation and quantification of key marker compounds, as outlined in Zhang et al. (15). Additionally, ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry was utilized to identify and confirm the chemical constituents of the granules. A total of 164 compounds were tentatively identified, including 44 flavonoids, 40 terpenoids, 43 alkaloids, 4 lignans, 2 coumarins, 2 alkyne derivatives, and 16 phenolic acids (Supplementary Figure 1, Supplementary Table 2). The identification was based on accurate mass data, retention times, and MS/MS fragmentation patterns, using established databases and literature references.

The placebo contained cyclodextrin and 5% of the active ingredients from the JQ granules, in line with previous studies that have demonstrated no significant pharmacological effects from this small percentage of active components (15, 21, 22). These studies were designed to ensure that the placebo was physiologically inert.

The experimental medication, JQ granules, and the corresponding placebo, which is a placebo of the JQ granules, are identical in packaging, appearance, color, smell, and dosage form. Both are uniformly labeled as “Clinical Research Medication” to ensure blinding integrity throughout the study. The administration guideline for both the JQ granules and placebo groups is standardized: participants are instructed to take one packet of the medication three times daily, at a one-hour interval after each meal.

The treatment duration for both groups is set at 4 weeks, with a subsequent 4-week follow-up period to monitor the long-term effects and safety of the intervention. To control for potential confounding factors, participants are required to abstain from any Chinese herbal compounds, Chinese patent medicines, acid suppressants, and prokinetic drugs for a minimum of 1 week prior to their enrollment in the study.

This study uses a double-blind design. Using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA), a randomization table was generated based on the allocation numbers and randomization ratios of the participating units. The experimental and control groups were assigned random codes in a 1:1 ratio. The selected block lengths and random seed parameters were kept confidential within the blinding protocol. Randomization is performed using SAS software version 9.4 by a statistician not directly affiliated with the clinical trial institution. Participants are randomly assigned to either the experimental group or the placebo group in a 1:1 ratio, and medications are numbered accordingly based on the generated random sequence for packaging. Subjects receive their study medications sequentially according to their enrollment order. Blinding is rigorously maintained for all parties involved, including physicians, data entry personnel, data managers, statisticians, and patients. The study uses a two-tier blinding code system. The level I blinding code indicates which drug numbers correspond to drug A or drug B, while the level II blinding code specifies whether drug A or B is the experimental drug or the placebo. Both blinding codes are held by the project management unit. The level I blinding code is provided to statisticians for analysis in accordance with the statistical analysis plan, enabling them to generate the statistical report. The second unblinding occurs during the summary meeting, where unblinding personnel sign the blinding code. The blinding codes are securely stored at the National Drug Clinical Trial Base Office at Xiyuan Hospital of the China Academy of Chinese Medical Sciences.

The primary outcomes of this study are the efficacy rates in alleviating symptoms like reflux and heartburn, and the corresponding changes in Visual Analog Scale (VAS) scores for these symptoms (15).

Secondary outcomes include a variety of assessments, such as changes in atypical symptom scores, total TCM syndrome scores, the efficacy of TCM syndrome improvements, variations in Gastroesophageal Reflux Disease Health-Related Quality of Life (GERD-HRQL) scale scores (23), shifts in the Chronic Gastrointestinal Disease Patient Reported Outcomes (PRO) Scale scores (24), and alterations in depression (SDS) and anxiety (SAS) scores (25, 26).

Safety detection indicators encompassed routine assessments of blood, urine, and stool, occult blood tests, liver function tests (encompassing alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), renal function tests (including blood urea nitrogen [BUN] and creatinine), and electrocardiograms. Adverse events or unintended toxic side effects (encompassing symptoms, signs, and laboratory findings) were meticulously monitored and reported. Each adverse event was analyzed and evaluated, followed by systematic tracking and documentation. Incidents occurring during the study were meticulously recorded in case report forms, detailing the symptoms, severity, onset time, duration, management measures, progression, and outcome, and assessing their correlation with the study medication.

The statistical analysis was designed based on prior research. The efficacy rate of JQ granules combined with low-dose omeprazole in treating NERD was reported to be 91% (15), while the average efficacy rate for placebo was documented as 60% (28, 29). The study aimed to conduct a superiority test for two independent proportions. Parameters for the test included a clinically significant difference (Δ) of 0.031, a significance level (α) of 0.05, and a power (β) of 0.2, with a 1:1 sample size ratio. Assuming a 20% loss to follow-up, the estimated sample size was 78 participants, with 39 in each group.

Demographic data and baseline indicators were analyzed to ensure comparability between the two groups. Compliance analysis was conducted to verify adherence to the prescribed drug regimen, documenting any deviations, including prohibited or concomitant medications.

For efficacy analysis, the primary efficacy indicators were evaluated using both per-protocol analysis and intention-to-treat analysis, with a primary focus on the full analysis set (FAS). Center effects on efficacy indicators were adjusted using the Cochran-Mantel-Haenszel (CMH) test, ensuring robust assessments. Additional statistical methods included the t-test, paired t-test, rank-sum test, paired rank-sum test, median test, Chi-square test, Fisher's exact test, and log-rank test. For confounding factors such as inter-group imbalance before treatment, the Cox proportional hazards model was applied to eliminate their influence on efficacy comparisons. Two-sided tests with a P ≤ 0.05 were considered statistically significant.

Safety analysis was performed using the safety analysis set (SS), providing a comprehensive evaluation of the safety profile of the trial drugs. Adverse effects were meticulously documented to ensure participant safety.

The first patient was enrolled on July 2, 2020, and the last patient was enrolled on December 30, 2021. A total of 78 subjects were enrolled in this study, with 39 in the placebo group and 39 in the JQ granules group, all of whom received at least one treatment and thus all entered the SS. Adhering to the intention-to-treat principle, 39 in the placebo group and 39 in the JQ granules group were included in the FAS. In the placebo group, 1 subject withdrew voluntarily, and another was non-compliant with medication; in the JQ granules group, 3 subjects withdrew voluntarily, 1 was non-compliant with medication, and 2 missed the follow-up visits within the prescribed period. Consequently, 37 in the placebo group and 33 in the JQ granules group were included in the PPS. The study workflow is presented in Figure 1.

In the placebo group, there were 18 males (46.15%) and 21 females (53.85%), with an average age of 48.49 ± 16.22 years and an average weight of 60.73 ± 9.85 kg. In the JQ granules group, there were 16 males (41.03%) and 23 females (58.97%), with an average age of 42.64 ± 14.49 years and an average weight of 63.86 ± 13.49 kg. The differences in demographic data between the two groups were not statistically significant (P > 0.05) (Table 1, Supplementary Table 5).

Additionally, there were no statistically significant differences between the two groups in terms of medication compliance, the number of concomitant medications used previously, the distribution of concomitant medications during the study period, past medical history, and history of allergies (P > 0.05) (Supplementary Table 6).

After a 4-week treatment period, the placebo group exhibited a reduction in SDS scores, yet this decrease was not statistically significant (P > 0.05). Conversely, the JQ granules group demonstrated a statistically significant reduction in SDS scores during the same timeframe (P < 0.0001). A statistically significant decrease in scores was noted for both groups at the 4-week follow-up, as compared to their initial assessments (P < 0.01 for both) (Table 8, Figure 6A). At the end of the 4-week treatment, the scores of the JQ granules group were marginally lower than those of the placebo group, nearing statistical significance (P = 0.0607) (Figure 6B). By the 4-week follow-up, no statistically significant difference in scores was observed between the JQ granules and placebo groups (P > 0.05), as shown in Figure 6B. Figure 6B depicts a consistent downward trend in SDS scores for both groups across all measured time points, with the JQ group possibly showing a greater improvement trend than the placebo group at both the 4-week treatment and follow-up.

Similarly, both the JQ granules and placebo groups experienced a significant reduction in SAS scores after 4 weeks of treatment and at the 4-week follow-up, relative to baseline (P < 0.05 for both), as indicated in Table 8 and shown in Figure 7A. No statistically significant differences in SAS scores were observed between the two groups at either the 4-week treatment or follow-up (P > 0.05) (Figure 7B). Figure 7B indicates a consistent decline in SAS scores for both groups, with a non-significant trend suggesting a potential advantage in the JQ granules group at the 4-week treatment and follow-up.

During the trial, no statistically significant differences were observed in the incidence of adverse events between the two groups (P > 0.05), as documented in Table 9. The JQ granules group reported a single adverse event, which recurred twice, presenting as oral blisters and an increase in phlegm production. This event was deemed a suspected adverse reaction, potentially related to the study medication. In contrast, the placebo group reported no adverse events. Comprehensive details regarding adverse events and reactions are provided in Supplementary Table 11. Both groups exhibited no abnormalities in vital signs, including heart rate, respiration, and blood pressure. Furthermore, no serious adverse events or complications were noted in either group.

GERD is a common upper gastrointestinal disorder with significant global prevalence and notable geographical variations, affecting ~13% of individuals with weekly symptoms (30). It imposes a substantial burden on healthcare systems and negatively impacts patients' quality of life. Despite its increasing prevalence, the clinical characteristics and natural history of GERD remain incompletely understood.

Historically, GERD has been classified into three subtypes: NERD, RE, and Barrett's Esophagus. This classification follows an older progressive disease model, which has been challenged by recent studies suggesting GERD encompasses a spectrum of disorders associated with gastroesophageal junction dysfunction (31, 32). Among GERD subtypes, NERD is the most common, accounting for ~70% of patients with reflux symptoms but no visible mucosal breaks on endoscopy (33). NERD exhibits significant heterogeneity in pathophysiological mechanisms, including acid exposure disorders, reflux hypersensitivity, and functional heartburn, with the latter two considered functional esophageal disorders. This classification is debated, as reflux hypersensitivity patients often present with microscopic esophagitis and reduced chemical clearance capacity, correlating strongly with non-acid reflux and symptom production. These patients also respond well to antireflux surgery, fitting the GERD definition (34). Some scholars advocate reclassifying reflux hypersensitivity within the GERD spectrum (34).

NERD management is complicated by the limitations of acid suppression therapy. While effective for patients with abnormal esophageal acid exposure, approximately 50% of NERD patients are refractory to such treatment, and symptom recurrence is common after discontinuation (5, 35). Long-term use of PPIs is associated with potential adverse effects, such as enteric infections, osteoporosis-related fractures, and chronic kidney disease, necessitating caution in maintenance therapy (4, 36–38). Although on-demand PPI therapy is proposed as an alternative, its effectiveness in NERD patients is based on low-level evidence, as highlighted in meta-analyses (37, 38).

TCM offers distinct advantages in treating NERD. Meta-analyses indicate that pure Chinese herbal medicine is more effective than single PPI or prokinetic drug treatments, with a lower recurrence rate compared to Western medicine (39). TCM classifies NERD as “regurgitation of acid” and “esophageal inflammation,” attributing the condition to a loss of stomach harmony and the upward reversal of stomach qi. Rooted in the principles of maintaining stomach harmony and reversing stomach qi, TCM emphasizes “descending and clearing” strategies.

This approach has led to the development of JQ granules for GERD characterized by spleen deficiency and damp-heat (15). The formula aims to strengthen the spleen, clear heat, and resolve dampness, targeting the condition's underlying pathophysiological mechanisms. Preliminary clinical trials show that JQ granules, combined with a low dose of omeprazole (10 mg), are more effective in relieving NERD symptoms than the standard dose (20 mg) (15). However, high-level evidence from randomized, double-blind, placebo-controlled studies for NERD is scarce. Most GERD research focuses on RE patients and faces limitations such as small sample sizes and single-center designs.

No prospective, multicenter, randomized, double-blind, placebo-controlled intervention trials have guided the treatment of NERD with the method of strengthening the spleen and clearing heat and dampness. This study aims to address these gaps by conducting a multicenter, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of JQ granules in treating NERD. This novel approach seeks to provide robust evidence supporting the integration of TCM into NERD management.

This study enrolled 78 participants, including 34 males and 44 females, yielding a gender-specific incidence ratio of 0.77:1. The predominance of NERD among females is consistent with prior research, which attributes the gender difference to biological and physiological variations. Male esophageal mucosa is reportedly more susceptible to duodenogastric reflux injury, often leading to RE, whereas females are more prone to gastroesophageal reflux symptoms characteristic of NERD (40–42).

Educational level emerged as a significant factor, with higher education identified as an independent risk factor for NERD (OR = 1.66, 95% CI 1.06–2.59) (43, 44). In this cohort, the ratio of participants with a college degree or above to those with lower educational levels was 1.33:1, consistent with prior research linking higher education to increased GERD prevalence.

The age distribution of participants was also consistent with previous reports. The mean ages in the JQ granules and placebo groups were 42.64 ± 14.49 years and 48.49 ± 16.22 years, respectively. GERD prevalence in China peaks between the ages of 40–49 and 50–59, with a decline observed in individuals over 60 (45). This pattern may reflect increased work pressure and unhealthy lifestyle habits among individuals in the over-40 age group, who represent the primary workforce.

In this study, the primary efficacy evaluation indicators revealed significant improvements in reflux and heartburn VAS scores among patients in the JQ granules group. The FAS analysis consistently demonstrated that JQ granules effectively ameliorated reflux and heartburn symptoms in NERD patients. At the 4-week treatment period, the JQ granules group showed a significantly higher efficacy rate (79.49%) than the placebo group (58.97%) (P < 0.05), confirming the positive therapeutic effect of JQ granules.

The efficacy rate for reflux symptoms after 4 weeks of treatment was 46.15% for the placebo group and 69.23% for the JQ granules group, with a statistically significant difference observed between the two groups (P = 0.0391). However, for heartburn efficacy, no significant difference was observed between the groups (53.85% for the placebo group and 58.97% for the JQ granules group, P = 0.6479), suggesting that JQ granules had a similar effect to placebo on heartburn symptoms.

At the 4-week follow-up, the overall efficacy rates were 61.54% for the placebo group and 71.79% for the JQ granules group, with no statistically significant difference (P = 0.3213). However, JQ granules showed a significantly higher efficacy rate for reflux improvement (71.79%) compared to the placebo group (48.72%) (P = 0.0373). This finding highlights that JQ granules can sustain therapeutic effects on reflux symptoms even after the treatment period. On the other hand, heartburn efficacy at the 4-week follow-up showed no significant difference between the two groups (56.41% for the JQ granules group vs. 51.28% for the placebo group, P = 0.6496), reinforcing the conclusion that JQ granules had no distinct advantage over placebo for heartburn relief during the follow-up.

The placebo response rate of 58.97% observed in this study aligns with findings from previous NERD trials. A meta-analysis of GERD trials reported placebo response rates ranging from 2.94% to 47.06%, with higher rates commonly observed in NERD due to its functional nature (46). The response rates for placebo in controlling regurgitation symptoms ranged from 20% to 60%, depending on the trial and the definition of a successful outcome used in each study (47). Similarly, a placebo-controlled trial of vonoprazan in NERD reported a heartburn-free day proportion of 61.50% in the placebo group (48), closely comparable to the placebo response rate in this study. These findings emphasize the substantial placebo response characteristic of NERD, where symptom relief is heavily reliant on subjective evaluations.

Several factors likely contributed to the notable placebo response in this study. First, NERD is characterized by the absence of visible mucosal injury, which makes symptom assessment more subjective and prone to variability. This inherent variability, combined with psychological factors such as patient expectations, may have contributed to the relatively high placebo response. Furthermore, as NERD is driven by mechanisms beyond just acid reflux, including non-acid reflux and digestive enzymes, symptom relief can often be perceived in the absence of objective biomarkers, leading to higher placebo response rates. Second, the structured design of the clinical trial may have amplified the placebo response. Regular patient monitoring, the use of placebos closely resembling the active drug, and detailed symptom tracking likely heightened participants' expectations of improvement. These methodological elements, inherent to randomized controlled trials, play a significant role in enhancing placebo responses. Third, the 4-week treatment period may have magnified transient placebo effects, as short-term symptom fluctuations are more likely to be perceived as improvement. This brief observation window may have also limited the ability to observe long-term divergence in efficacy rates between the groups. Finally, the placebo used in this study contained a relatively high amount of cyclodextrin, which may have contributed to the observed placebo response. Cyclodextrins are known to form inclusion complexes with hydrophobic molecules, potentially reducing esophageal irritation caused by refluxate. Additionally, their mucoadhesive properties may enhance the mucosal barrier, providing a mild protective effect (49–52). These unintended effects, combined with the psychological impact of participating in a structured clinical trial, may have amplified the placebo response.

Despite the significant placebo response, JQ granules demonstrated superior efficacy compared to placebo (79.49% vs. 58.97%, P < 0.05), particularly in improving reflux symptoms, which were significantly better at both the 4-week treatment and 4-week follow-up periods. These results suggest that JQ granules have therapeutic potential in NERD, offering clinical benefits, especially in alleviating reflux symptoms. However, the heartburn response in this study was less distinct, and further studies with larger sample sizes and longer follow-up periods are warranted to further investigate the effects of JQ granules on heartburn relief and explore their long-term efficacy.

The challenges of treating GERD-related reflux symptoms with current therapies, particularly PPIs, highlight the potential advantages of JQ granules. Acid-suppressing therapy, while effective in reducing acidic reflux events, does not significantly decrease the occurrence of overall reflux events. Furthermore, it may transform acidic reflux into weak acid or alkaline reflux, which is often associated with a shift from heartburn to persistent reflux symptoms (53). Studies have shown that only 26%−44% of GERD patients with reflux as the main symptom respond to PPI treatment, with a response rate only 17% higher than placebo (47, 54).

Alternative therapies, such as baclofen, have been studied for PPI-refractory reflux. Baclofen, a gamma-aminobutyric acid B receptor agonist, reduces reflux events by inhibiting transient lower esophageal sphincter (LES) relaxations and increasing LES resting pressure. However, while it decreases the number of reflux events, it does not effectively improve patient symptoms and is associated with significant side effects, such as dizziness, drowsiness, and constipation, limiting its clinical use (55). Additionally, baclofen has not been approved by the U.S. Food and Drug Administration for the treatment of GERD, and long-term efficacy studies are lacking (56, 57). Consequently, refractory reflux symptoms that do not respond well to acid suppression therapy remain a significant challenge in GERD management.

The significant alleviation of reflux symptoms observed with JQ granules suggests that this treatment may offer distinct advantages, particularly for NERD patients with reflux-dominated symptoms. Unlike conventional therapies, JQ granules appear to address limitations associated with existing treatment options and may be especially beneficial for patients with non-acid reflux. Nonetheless, further research, particularly using multichannel intraluminal impedance-pH monitoring, is warranted to comprehensively evaluate the efficacy and mechanism of JQ granules in this context.

This study evaluated the effects of JQ granules on extraesophageal symptoms of NERD, such as cough and asthma. The placebo group showed no significant changes in cough frequency and severity scores from baseline (P > 0.05), whereas the JQ granules group demonstrated a significant reduction in these scores (P < 0.01). Similarly, asthma frequency scores increased in the placebo group compared to baseline (P > 0.05) but decreased in the JQ granules group, though this reduction did not reach statistical significance (P > 0.05). Despite the lack of statistically significant differences between the groups, the within-group analysis revealed a greater degree of improvement in both symptoms for the JQ granules group.

The observed improvement in respiratory symptoms in the JQ granules group corresponds with the reduction in reflux symptoms. Extraesophageal symptoms, particularly respiratory manifestations, are known to respond less effectively to acid-suppressive therapy compared to typical symptoms like reflux and heartburn. This may be due to the sensitivity of the upper airway structures, such as the throat, larynx, and pharynx, to non-acidic factors including weak acid reflux, weak alkaline reflux, gas reflux, pepsin, and bile salts. Research indicates that only 10% of extraesophageal symptoms are related to acid reflux, whereas up to 40% are associated with non-acid reflux events. Acid-suppressive agents, such as PPIs, reduce heartburn by lowering refluxate acidity but do not prevent non-acid reflux events or protect against airway aspiration (58–61).

The increased frequency of non-acid reflux events associated with acid-suppressive therapy may exacerbate respiratory symptoms through microaspiration and esophago-tracheo-bronchial reflexes (62). This study suggests that JQ granules may provide potential benefits for respiratory symptoms linked to NERD, potentially addressing the limitations of acid-suppressive therapy. However, their efficacy in treating PPI-refractory respiratory symptoms requires further validation in large-scale clinical studies using PPI as a positive control.

This study demonstrated a significant improvement in TCM syndrome scores in the JQ granules group, with a 69.23% improvement rate compared to 46.15% in the placebo group after 4 weeks of treatment (P < 0.05). However, during the 4-week follow-up period, the efficacy rate in the JQ granules group declined to 53.85%, while the placebo group showed a slight increase to 56.41%. This unexpected trend, with no statistically significant difference between groups (P = 0.8978), may be explained by several factors.

First, the increase in the placebo group's efficacy rate during follow-up could be attributed to delayed placebo effects or natural symptom variability, both of which are common in NERD. Some placebo participants may have experienced transient symptom improvement due to natural fluctuations or psychological factors associated with their involvement in the trial. Second, the small sample size may have amplified these changes, as minor numerical shifts in patient responses can disproportionately affect percentage calculations. Lastly, the placebo composition, containing cyclodextrin, may have contributed to sustained symptom relief in some participants due to its potential mucosal protective effects. These findings underscore the importance of exploring longer-term treatment strategies, including the potential role of maintenance therapy with JQ granules.

Although the reduction in TCM syndrome scores after 4 weeks of treatment in the JQ granules group approached statistical significance compared to the placebo group (P = 0.0781), the results highlight the therapeutic potential of strengthening the spleen, clearing heat, and resolving dampness in managing the pathophysiological features of NERD. These findings align with the effectiveness of TCM strategies in alleviating symptoms associated with spleen deficiency and damp-heat syndrome.

Microscopic mucosal changes, despite the absence of visible mucosal erosions in NERD patients, are critical in the disease's pathophysiology. High-definition magnification endoscopy can detect subtle mucosal alterations, such as edema, indistinct vascular patterns, and patchy unevenness. Histological findings often reveal microscopic esophagitis, including basal cell hyperplasia, elongated papillae, intraepithelial inflammatory cell infiltration, and dilated intercellular spaces (DIS), which are hallmarks of diminished mucosal integrity (63).

The compromised mucosal barrier in NERD facilitates the penetration of noxious substances like pepsin and bile, triggering mast cell degranulation, histamine release, and peripheral sensitization (64, 65). DIS is prevalent in 68.2%−83% of NERD patients and plays a pivotal role in esophageal sensitivity to refluxants, including non-acidic or weakly acidic reflux. This sensitivity underscores the limited efficacy of PPI treatment in NERD patients with DIS and highlights the need for alternative approaches (66–73).

Consensus suggests that spleen damp-heat syndrome, manifesting in various aspects including the immune system, gastrointestinal motility, and microecology, is closely associated with inflammation (74). A large cross-sectional study (n = 1,000) indicates that the prevalence of microscopic mucosal changes in endoscopy among spleen damp-heat type NERD patients is significantly higher than in other syndrome types, implying a close relationship between spleen damp-heat syndrome and mucosal microscopic changes in NERD (75).

TCM's spleen damp-heat syndrome provides a theoretical basis for JQ granules' mechanism of action. Previous mechanistic studies have confirmed that JQ granules can enhance the proliferation and activation of mast cells in the esophageal mucosa of GERD models, reduce nerve ending sensitization, and improve mucosal barrier function (76). Although pathological histology was not included in this study, the symptom improvement observed with JQ granules suggests a potential role in addressing microscopic mucosal changes in spleen damp-heat type NERD patients.

Future research will focus on histopathological assessments of esophageal mucosa to elucidate the impact of JQ granules on microscopic lesions and their correlation with symptom improvement. This approach will help further validate the therapeutic benefits of JQ granules in NERD management and deepen the understanding of their mechanism of action.

The GERD-HRQL scale scores revealed no statistically significant differences between the JQ granules and placebo groups after 4 weeks of treatment or at the 4-week follow-up (P > 0.05). However, within-group analyses demonstrated a significant reduction in scores from baseline over time in both groups (JQ granules: P < 0.001; placebo: P < 0.01). Although the JQ granules group exhibited a more pronounced improvement compared to the placebo group, this difference did not reach statistical significance, potentially due to the limited sample size and the short treatment and follow-up durations.

The Chronic Gastrointestinal Disease PRO Scale, widely recognized for its reliability and validity in evaluating conditions such as NERD, revealed no statistically significant differences between the groups in scores for dyspepsia, bowel irregularity, psychological mood, or the total PRO Scale score at 4 weeks post-treatment and at the follow-up (P > 0.05). Despite this, there was a non-significant trend favoring the JQ granules group in the reflux and bowel irregularity dimensions, as well as in the total PRO Scale score.

For the reflux dimension, within-group analyses showed a significant reduction in scores from baseline in the JQ granules group at both 4 weeks post-treatment and the follow-up (P < 0.01). In contrast, the placebo group showed no significant change in reflux scores at the follow-up (P > 0.05). Between-group comparisons revealed a nearly statistically significant difference in reflux score improvements from baseline to 4 weeks post-treatment favoring the JQ granules group (P = 0.06735). This suggests a potential advantage of JQ granules in alleviating reflux symptoms, consistent with the main efficacy indicators.

In the social functioning dimension of the PRO Scale, the placebo group exhibited no significant improvement from baseline after 4 weeks of treatment (P > 0.05), whereas the JQ granules group demonstrated a significant improvement (P < 0.01). Between-group comparisons further revealed that the JQ granules group had significantly lower scores than the placebo group at both 4 weeks post-treatment and at the follow-up (P < 0.05), indicating that JQ granules may effectively enhance social functioning in NERD patients.

These findings suggest that JQ granules show promise in improving certain dimensions of quality of life, particularly social functioning and reflux-related symptoms.

This study examined the impact of JQ granules on psychological symptoms, such as anxiety and depression, in NERD patients. Both the JQ granules and placebo groups showed significant reductions in anxiety scores after 4 weeks of treatment and at the 4-week follow-up compared to baseline (P < 0.05 for both). However, the differences in anxiety scores between the two groups and the within-group changes in the JQ granules group did not reach statistical significance (P > 0.05).

For depression, within-group comparisons revealed no significant change in the placebo group's scores after treatment (P > 0.05), while the JQ granules group experienced a significant reduction in depression scores (P < 0.0001). Between-group comparisons showed that the JQ granules group's depression scores were lower than those of the placebo group, with the difference approaching statistical significance (P = 0.0607). These results suggest that JQ granules may have a beneficial effect on depressive symptoms in NERD patients.

Psychological symptoms, including anxiety and depression, are prevalent among GERD patients, with even higher rates in NERD patients compared to those with RE. In Chinese populations, the prevalence of anxiety and depression in NERD patients is reported at 51% and 45%, respectively (77). These symptoms exacerbate peripheral and central sensitivity, diminishing the effectiveness of acid suppression therapies and creating a cycle that worsens symptoms and quality of life, especially in NERD patients. Factors such as heightened sensitivity through the brain-gut axis and lowered sensory thresholds play crucial roles in NERD pathophysiology, with depression identified as a significant risk factor for worsening gastroesophageal reflux symptoms (78–82).

Emerging evidence links variations in gut microbiota composition to the interplay between GERD and psychological comorbidities. Firmicutes and Bacteroidetes are characteristic gut microbiota in NERD patients with psychological symptoms (83). JQ granules combined with low-dose PPI therapy (omeprazole 10 mg) have shown greater efficacy in improving psychological states compared to standard-dose PPI therapy (omeprazole 20 mg) (15). This combination therapy also significantly modulates the relative abundance of Firmicutes and Bacteroidetes, providing further evidence of the potential of JQ granules to alleviate psychological symptoms—particularly depressive symptoms—through the regulation of gut microbiota (15).

This study confirmed the safety and efficacy of JQ granules in treating NERD. No significant effects on vital signs, the circulatory system, or liver and kidney function were observed, and no severe adverse events or complications occurred. Additionally, the incidence of adverse events was comparable between the JQ granules and placebo groups during treatment and follow-up (P > 0.05), highlighting the favorable safety profile of this herbal therapy.

In terms of efficacy, JQ granules demonstrated significant advantages over placebo, particularly in improving primary symptoms such as reflux. The treatment effectively addressed the pathophysiological features of NERD, showing greater efficacy in managing spleen deficiency and damp-heat syndrome compared to placebo. Furthermore, JQ granules exhibited trends of improvement in secondary symptoms, including TCM syndrome scores, GERD-HRQL scale scores, and the reflux and bowel irregularity dimensions of the PRO Scale, as well as anxiety and depression. The potential mechanisms underlying these effects involve the restoration of mucosal integrity and the modulation of gut microbiota. JQ granules enhance the esophageal mucosal barrier by promoting mast cell activation, reducing nerve sensitization, and mitigating esophageal permeability caused by DIS (76). These processes likely reduce sensitivity to refluxants, contributing to the relief of both acidic and non-acidic reflux symptoms. Additionally, by regulating the relative abundance of Firmicutes and Bacteroidetes, JQ granules may help restore gut microbiota balance (15). This effect is particularly relevant in NERD patients who present with psychological symptoms, as the modulation of gut microbiota is associated with improvements in both gastrointestinal and psychological outcomes.

This study highlights the potential of JQ granules as a treatment for NERD, demonstrating significant efficacy in alleviating reflux symptoms. However, further research is needed to explore several key areas.

First, evaluating the efficacy of JQ granules in different subtypes of NERD (e.g., abnormal acid exposure, reflux hypersensitivity, and functional heartburn) will help tailor treatment strategies to specific patient populations. Investigating the impact of disease duration and using larger sample sizes will also enhance the generalizability of the findings, providing a clearer understanding of the long-term benefits of JQ granules. Additionally, combination therapies, particularly with low-dose PPIs, have shown promise in preliminary studies (15), and future trials should explore synergistic effects with other pharmacological agents, such as potassium-competitive acid blockers, antidepressants, and alginate, especially in patients with rGERD or psychological comorbidities.

While the findings from this study were promising, several factors may have influenced the observed efficacy and warrant further exploration. The small sample size, based on prior research estimates, may have limited the statistical power to detect significant differences. Increasing sample size in future trials would improve statistical robustness, particularly in heterogenous disorders like NERD, where symptom variability is more pronounced.

The impact of the COVID-19 pandemic on patient enrollment and follow-up data is another consideration. Disruptions caused by the pandemic may have introduced additional variability in the data, which could have affected the precision of the results. Future studies with extended follow-up periods and more consistent patient data collection are needed to assess long-term outcomes more accurately.

The high placebo response observed in this study, particularly for reflux symptoms, is common in NERD trials due to the functional nature of the disorder. Psychological factors, patient expectations, and natural symptom fluctuations play a substantial role in symptom relief. The placebo used in this study contained cyclodextrin, which may have further amplified the placebo response due to its mucoadhesive properties and potential to reduce esophageal irritation, suggesting that future studies should consider placebo formulations more carefully.

Finally, future research should include longer treatment and follow-up periods to capture the full therapeutic potential of JQ granules. Extended treatment durations would allow for sustained therapeutic effects and provide a better understanding of the long-term benefits. Further exploration into esophageal histopathology is essential to assess the impact of JQ granules on microscopic mucosal changes and their correlation with symptomatic improvement. Investigating molecular pathways related to mucosal barrier function and gut microbiota regulation will provide deeper insights into their mechanisms of action. Specific targets, including mucosal-specific activation protein kinase 2, substance P, and calcitonin gene-related peptide, may clarify how JQ granules alleviate NERD symptoms and improve patient outcomes.